Our published and preliminary results, in the current funding period, support the idea that the role of Akt in energy metabolism is coupled to its role in the genesis of cancer. We have provided experimental evidence that the ability of Akt to inhibit apoptosis is dependent, at least in part, on mitochondrial hexokinases, which catalyze the first committed step in glycloysis and couple oxidative phosphorylation and glycolysis. Our results showed that the role of Akt in cell proliferation and susceptibility to oncogenic transformation is also coupled to its role in energy metabolism. We have shown that the most critical downstream effector of Akt, required for cell proliferation and susceptibility to oncogenic transformation is mTORC1. Akt activates mTORC1, at least in part, via the increase in intracellular ATP and the inactivation of AMPK, which otherwise inhibits mTORC1 activity. The ability of activated Akt to increase energy metabolism is also associated with accelerated ROS production. In addition, Akt inhibits ROS degeneration by inhibiting FoxO. The excessive accumulation of ROS mediated by Akt could certainly contribute to the genesis of cancer by increasing genetic instability. However, this is also the Achilles heel of Akt since Akt cannot protect from ROS-induced apoptosis and thus in contrast to its ability to inhibit apoptosis in general, Akt sensitizes to killing by ROS. This provides a rationale for a strategy intended to selectively eradicate cancer cells with activated Akt and to evade Akt-induced resistance to chemotherapy. Intriguingly, our preliminary results showed that glucose and hexokinases, and in particular hexokinase II (HKII), can induce pro-oncogenic signaling pathways. We propose to delineate mechanistically this pro-oncogenic activity of HKII. Other preliminary results provided us with the opportunity to examine the roles of Akt isoforms and HKII in the development of HCC, and therefore the implications for HCC therapy. We will employ Akt1, and Akt2 KO mice as well as conditional HKII KO mice to address these issues. PUBLIC HEALTH RELEVANCE: Studies in this grant application are intended to provide strategies for cancer therapy, and to evade chemoresistance induced by the most frequently activated pathway in human cancer. Studies are also intended to delineate the role of this pathway in the development of hepatocellular carcinoma.